Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.[OH-].[Li+]>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Sc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2ccc(Cl)cc2)nc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
6-Chloro-3-nitropyridine (4.0 grams) and 4-chlorothiophenol (3.7 grams) were mixed in 100 ml. of dry DMF and lithium hydroxide (1.2 grams) added portionwise. After the reaction mixture had stirred for about 5 minutes, it darkened and became warm. It was allowed to stir with a drying tube for 4 hours, poured over ice water and the product separated by filtration. It was crystallized from ethyl acetate-ethanol, yield: 5.0 grams, m.p. 134°-136° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][N:9]1[CH2:18][CH2:19][NH2:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:21]([NH:20][CH2:19][CH2:18][N:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCN1Cc2ccccc2CC1Cc1ccccc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: c1ccc(CNCCN2Cc3ccccc3CC2Cc2ccccc2)cc1
Reaction time: 8 h
Yield: 70.1 %

Procedure:
26 mg of 2-[3-benzyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine was dissolved in 1 mL of toluene, and MS-4A (30 mg), 10.4 mg of benzaldehyde, 18 mg of sodium triacetoxyborohydride, and 0.01 mL of acetic acid were added thereto at room temperature, followed by stirring overnight. After completion of the reaction, to the reaction liquid was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified using PLC (chloroform:methanol=20:1) to obtain 24.4 mg (yield 70%) of a title compound as a pale yellow oily substance.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:24])[C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][CH:10]=2)=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].O>O1CCCC1.CN(C)C=O>[F:1][C:2]1[C:3]([OH:26])=[CH:4][CH:5]=[C:6]([F:25])[C:7]=1[C:8]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)=[O:24]
Reactant: Oc1ccc(F)c(C(O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(c1c(F)ccc(O)c1F)c1c[nH]c2ncc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 50 h

Procedure:
To 2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenol (P-0009, 45.0 mg, 1.27 mmol) in tetrahydrofuran (15 mL) and N,N-dimethylformamide (5 mL) was added dichlorodicyanoquinone (87 mg, 3.8 mmol). The reaction was stirred at room temperature for 50 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 5% methanol in methylene chloride to give a white solid (P-0066, 7 mg, 15.6%). MS (ESI) [M+H+]+=352.1.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:22]([F:25])([F:24])[F:23])=[N:20][N:21]=3)[N:18]=2)[CH2:11][CH:12]=1)(=O)=O.[OH:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[F:23][C:22]([F:25])([F:24])[C:19]1[N:17]2[N:18]=[C:13]([N:10]3[CH2:11][CH:12]=[C:7]([C:33]4[CH:34]=[C:29]([OH:28])[CH:30]=[CH:31][CH:32]=4)[CH2:8][CH2:9]3)[CH:14]=[CH:15][C:16]2=[N:21][N:20]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: O=S(=O)(OC1=CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1)C(F)(F)F
Product: Oc1cccc(C2=CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Yield: 72 %

Procedure:
Obtained in 72% yield by an analogous procedure to Example 605, starting from 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate and 3-hydroxyphenylboronic acid.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:7][C:8](O)=O)[CH2:3][C:4]([OH:6])=[O:5].[CH3:12][CH:13]=C(C)C.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].C(N(CC)CC)C>C(Cl)(Cl)Cl.O1CCCC1>[N:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:24][C:8]=1[CH2:7][C:2]([CH3:1])([CH3:11])[CH2:3][C:4]([O:6][CH2:12][CH3:13])=[O:5]
Reactant: CC(C)(CC(=O)O)CC(=O)O
Reactant: CC=C(C)C
Reactant: Nc1ccccc1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(C)Cc1nc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 139.2 of the acid chloride ethyl ester of 3,3-dimethylglutaric acid, prepared in Example 28, in 125 ml of chloroform, stabilized with amylene, is added dropwise, at a temperature of between 5° C. and 10° C., to a solution of 72.8 g of orthophenylenediamine and 112 ml of triethylamine in 1 l of anhydrous tetrahydrofuran. The mixture is stirred at 0° C. for two hours and then at 50° C. for one hour; the crystals are filtered off and the solvents are evaporated off under vacuum. The residue is taken up in 4.4 1 of ethanol and 444 ml of concentrated hydrochloric acid and the mixture is refluxed for 12 hours. The solvents are evaporated off and the residue is taken up with water and then neutralized with a 1 N solution of sodium hydroxide and extracted with ether. The ether phase is dried and then evaporated under vacuum to give 99 g of ethyl 4-(benzimidazol-2-yl)-3,3-dimethylbutanoate in the form of crystals melting at 123° C.
Reaction SMILES: [CH:1]1([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:26]([O:28]C)=[O:27])[CH:20]=4)[NH:15]3)=[CH:10][CH:9]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=4)[NH:15]3)=[CH:10][CH:9]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)C3CCC3)cc1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(NC(=O)C2CCC2)cc1
Yield: 37.7 %

Procedure:
To a mixture of methyl 2-(4-(cyclobutanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (42 mg, 0.21 mmol) in methanol (3 mL) and water (1.5 mL) was treated with a solution of sodium hydroxide (133 mg, 2.63 mmol) in water (1.5 mL). The resultant mixture was heated to reflux until the completion of the reaction (monitored by thin layer chromatography). The methanol was removed under vacuum. The residue was acidified with 2M hydrochloric acid to pH=1. The precipitates were collected by filtration to afford 30 mg of 2-(4-(cyclobutanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow solid Yield: 84%. MS (ESI+APCI) M+1=379.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][C:3]=1[OH:13].[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[C:5]([Cl:12])=[CH:4][C:3]=1[OH:13])=[O:18]
Reactant: O=C(O)c1ccncc1Cl
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc(C(F)(F)F)c(Cl)cc1O)c1ccncc1Cl
Temperature: 80 °C
Yield: 57.3 %

Procedure:
A mixture of 0.50 g of 2-amino-5-chloro-4-trifluoromethylphenol, 0.36 g of 3-chloroisonicotinic acid, 0.56 g of WSC and 5 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.46 g of 3-chloro-N-[4-chloro-2-hydroxy-5-trifluoromethylphenyl]isonicotinamide.
Reaction SMILES: [ClH:1].[CH:2]1([CH2:8][C:9]([C:11]2[N:12]=[C:13]([CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[S:14][CH:15]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>O1CCOCC1.C(OCC)C>[Cl-:1].[CH:2]1([CH2:8][C:9]([C:11]2[N:12]=[C:13]([CH:16]3[CH2:17][CH2:18][NH2+:19][CH2:20][CH2:21]3)[S:14][CH:15]=2)=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)CC3CCCCC3)cs2)CC1
Reactant: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(CC1CCCCC1)c1csc(C2CC[NH2+]CC2)n1
Product: [Cl-]
Temperature: 0 °C

Procedure:
Under argon and at 0° C., a solution of hydrogen chloride in dioxane (4M, 1 ml) was added to a solution of tert-butyl 4-[4-(cyclohexylacetyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (5.0 g) in diethyl ether (1 ml). The mixture was stirred at 0° C. and then slowly warmed to room temperature. After stirring overnight, excess acid and the solvent were removed under reduced pressure. This gave 4[4-(cyclohexylacetyl)-1,3-thiazol-2-yl]piperidinium chloride (315 mg).
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:23]1[CH2:32][O:31][C:30]2[CH:29]=[CH:28][C:27](Br)=[CH:26][C:25]=2[O:24]1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41][CH:42]([OH:45])[CH:43]=[CH2:44])[CH:35]=1>C(N(CC)CC)C.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:31]1[C:30]2[CH:29]=[CH:28][C:27]([CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH2:40][C:36]3[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=3)=[CH:26][C:25]=2[O:24][CH2:23][CH2:32]1.[O:31]1[C:30]2[CH:29]=[CH:28][C:27](/[CH:44]=[CH:43]/[CH:42]([OH:45])[CH2:41][CH2:40][C:36]3[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=3)=[CH:26][C:25]=2[O:24][CH2:23][CH2:32]1
Reactant: Brc1ccc2c(c1)OCCO2
Reactant: C=CC(O)CCc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CCc1cccnc1)CCc1ccc2c(c1)OCCO2
Product: OC(/C=C/c1ccc2c(c1)OCCO2)CCc1cccnc1
Temperature: 80 °C

Procedure:
A mixture of palladium(II) acetate (0.112 g), tri-o-tolylphosphine (0.304 g), 3,4-ethylenedioxybromobenzene (1.075 g) and (±)-5-(pyridin-3-yl)-1-penten-3-ol (0.815 g, Example 1a)) in triethylamine (10 ml) in acetonitrile (30 ml) was heated at 80° C. for 3 hours and 30 minutes. The mixture was cooled to room temperature and filtered through Celite® and the filtrate concentrated under reduced pressure. The residue was redissolved in ethyl acetate and the solution washed with water then dried over anhydrous magnesium sulfate. The solution was then filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with hexane:acetone (3:1) then (2:1) to give firstly 1-(benzo-1,4-dioxan-6-yl)-5-(pyridin-3-yl)-3-pentanone as an oil (0.812 g) and secondly (±)-trans-1-(benzo-1,4-dioxan-6-yl)-5-(pyridin-3-yl)-pent-1-en-3-ol as an oil (0.252 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:7]([CH3:16])[C:6]([N+:17]([O-:19])=[O:18])=[CH:5][CH:4]=1.C=O.C[C:23](C)([O-:25])C.[K+]>CS(C)=O>[CH3:1][O:2][C:3]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:7]([CH2:16][CH2:23][OH:25])[C:6]([N+:17]([O-:19])=[O:18])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(C)c1N1CCN(C)CC1
Reactant: CC(C)(C)[O-]
Agent: C=O
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc([N+](=O)[O-])c(CCO)c1N1CCN(C)CC1
Temperature: 72.5 °C
Yield: 111.9 %

Procedure:
A mixture of 1-(6-methoxy-2-methyl-3-nitrophenyl)-4-methylpiperazine (D30) (360 mg, 1.36 mmol), dry dimethylsulfoxide (3 ml), paraformaldehyde (82 mg, 2.72 mmol) and potassium tert-butoxide (52 mg, 0.46 mmol) was heated at 70-75° C. for 30 h. After cooling, the mixture was partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) evaporated under reduced pressure and purified by chromatography on silica gel, eluting with methanol and dichloromethane, to give the title compound (D31) as a yellow solid (152 mg, 38%) MH+=296.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=O>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][CH2:25][C:24]([O:28][CH2:29][CH3:30])=[O:27])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C=O
Reactant: CCOC(=O)C(CCc1ccccc1N)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CNc1ccccc1CCC(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of ethyl 2-t-butyloxycarbonylamino-4-(2-aminophenyl)butyrate (10.0 g) and ethyl glyoxylate (4.2 g) in ethanol (120 ml) is hydrogenated at 80° and 3 atmospheres pressure for 72 hours using 10% palladium on charcoal (3 g) as catalyst. The reaction mixture is cooled to room temperature and the catalyst filtered off. The solvent is removed under reduced pressure and the residue distributed between ethyl acetate (150 ml) and water (75 ml). The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure to give ethyl 2-t-butyloxycarbonylamino-4-[o-(ethoxycarbonylmethylamino)phenyl]butyrate which is used without further purification for the next step.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C.CCCP(=O)=O>CN(C=O)C.O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:25])[NH:10][C:7]2[CH:8]=[CH:9][C:4]3[N:3]=[CH:2][S:1][C:5]=3[CH:6]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1ccc2ncsc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc3ncsc3c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.9 %

Procedure:
A mixture of benzothiazol-6-ylamine (0.15 g, 1 mmol) and piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.23 g, 1 mmol) in DMF (3 ml) was treated with DIPEA (5 eq.) and propylphosphonic anhydride (1 eq, 50% solution in EA). The mixture was stirred at rt for 72 h, diluted with water and extracted with EA. The org. layers were washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by chromatography on SiO2 (hex/EA 1:1, EA) to give the coupling product as a colourless oil (0.22 g, 61% yield).
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH3:22].[CH3:23][C:24]([CH3:26])=O>CO>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH3:22])[N:6]([CH2:5][CH2:4][CH2:3][O:2][N:1]=[C:24]([CH3:26])[CH3:23])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(C)=O
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCON
Solvent: CO
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCON=C(C)C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A mixture of 1-[3-(aminooxy)propyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 1, 0.605 g, 2.02 mmol) in methanol was heated until the starting material dissolved. Acetone (3 mL, 40 mmol) was then added, and the resulting solution was stirred for two hours. The reaction was then concentrated under reduced pressure, and the residue (800 mg) was purified by column chromatography on silica gel (25 g, eluting sequentially with 98:2 dichloromethane:methanol and 95:5 dichloromethane:methanol) to provide 600 mg of acetone O-[3-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]oxime as a beige powder, mp 147-150° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([F:9])=[C:7](F)[N:6]=[C:5]([F:11])[C:4]=1[F:12].[CH3:13][NH:14][CH3:15].O>C(O)C>[CH3:13][N:14]([CH3:15])[C:7]1[C:8]([F:9])=[C:3]([CH2:2][OH:1])[C:4]([F:12])=[C:5]([F:11])[N:6]=1
Reactant: CNC
Reactant: OCc1c(F)c(F)nc(F)c1F
Solvent: O
Solvent: CCO
Product: CN(C)c1nc(F)c(F)c(CO)c1F
Yield: 87.3 %

Procedure:
A mixture of 1.0 g (0.0055 mole) of 4-hydroxymethyl-2,3,5,6-tetrafluoropyridine (from Example 5) and 0.23 g (0.0050 mole) of dimethylamine in 25 ml of ethanol was refluxed for approximately twenty hours. The reaction mixture was cooled and was poured into water. This mixture was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated under reduced pressure, yielding 0.9 g of 2-dimethylamino-4-hydroxymethyl-3,5,6-trifluoropyridine as a yellow oil. The structure and nmr spectra are set forth in Table 1C below.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][S:11]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)(=[O:13])=[O:12])=[O:9])=[CH:4][CH:3]=1.[N:20]([C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25](OC)=[O:26])=[C:21]=[O:22].C1CCN2C(=NCCC2)CC1>C1COCC1>[O:22]=[C:21]1[N:1]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([NH:10][S:11]([C:14]3[S:15][C:16]([Cl:19])=[CH:17][CH:18]=3)(=[O:13])=[O:12])=[O:9])=[CH:4][CH:3]=2)[C:25](=[O:26])[C:24]2[C:23](=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH:20]1
Reactant: COC(=O)c1ccccc1N=C=O
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccc(Cl)s2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=C(NS(=O)(=O)c1ccc(Cl)s1)c1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Reaction time: 18 h
Yield: 34 %

Procedure:
A 44 mg portion (0.14) of (4-aminophenyl)-N-[(5-chloro(2-thienyl))sulfonyl]carboxamide was combined with 25 mg (0.14 mmol) of methyl 2-isocyanatobenzoate in 500 uL of THF followed by the addition of 1 equivalent of TEA (24 μL) and 1 equivalent of DBU. After 18 h, the mixture was purified by RP-HPLC, to give 21 mg (34%) of the desired compound. ES-MS (M+H)+=462 (Cl).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Cl:6][CH2:7][Si:8]([CH3:18])([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.O>C1(C)C(C)=CC=CC=1>[ClH:6].[CH3:7][Si:8]([CH2:18][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1
Reactant: c1nc[nH]n1
Reactant: C[Si](C)(CCl)Cc1ccc(F)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: C[Si](C)(Cc1ccc(F)cc1)Cn1cncn1
Product: Cl

Procedure:
After adding 10 g of 1,2,4-triazole to 10.8 g of chloromethyl-dimethyl-(4-fluorobenzyl)silane dissolved in 50 ml of xylene, the reaction mixture is refluxed for 8 hours, then 200 ml of water are added and the phases are separated. The organic phase is washed 3 times with a total of 150 ml of water, dried over anhydrous magnesium sulfate and after filtration the filtrate is evaporated to solvent-free. The pale yellow oily residue is dissolved in 70 ml of methyl propyl ketone, the solution is acidified to pH 4.5 by adding methanolic hydrogen chloride solution and then concentrated to a volume of 40 ml by distillation under atmospheric pressure. The crystals precipitated are filtered at 0° C. to give the named product in a yield of 6.56 g (46%), m.p.: 113°-114° C.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][CH2:11][CH:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:9]1=[O:27]>C(Cl)Cl>[Cl:3][CH2:6][CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][CH2:11][CH:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:9]1=[O:27]
Reactant: COc1ccc(C2CSc3ccccc3N(CCO)C2=O)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C2CSc3ccccc3N(CCCl)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.14 ml of thionyl chloride was added to a solution of 329 mg of the product of Step C in 3.3 ml of methylene chloride and the mixture was stirred for 15 minutes at ambient temperature, then evaporated to dryness under reduced pressure. The residue was taken up in 25 ml of ether at reflux, treated with activated charcoal, filtered and concentrated to 7 ml. After separation, 300 mg of the expected product melting at approx. 70° C. were obtained which was used as is for Step E. An analytical sample was prepared by dissolving 300 mg of the product in 10 ml of hot methyl ethyl ketone which was concentrated to 2 ml, then adding 2 ml of pentane. After separating, 65 mg of the desired product melting at approx. 70° C. were obtained.
Reaction SMILES: C(C1(C2C=CC([Cl:14])=CC=2)CCC1)(=O)C.[C:15]([C:18]1([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24](Cl)[CH:23]=2)[CH2:21][CH2:20][CH2:19]1)(=O)[CH3:16].C(O)=O.[CH:33]([NH:36]C=O)([CH3:35])[CH3:34]>Cl>[ClH:14].[CH:33]([NH:36][CH:15]([C:18]1([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][CH2:19]1)[CH3:16])([CH3:35])[CH3:34]
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCC1
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: CC(C)NC=O
Agent: Cl
Solvent: O=CO
Product: CC(C)NC(C)C1(c2ccc(Cl)cc2)CCC1
Temperature: 180 °C

Procedure:
1-Acetyl-1-(4-chlorophenyl)cyclobutane (10. 4 g) prepared in a similar manner to that described in Example 1 for 1-acetyl-1-(3,4-dichlorophenyl)cyclobutane and 98% formic acid (5 ml) were added to N-isopropylformamide (43.5 g) and the mixture heated at 180° C. for four hours. Excess starting material was distilled off under reduced pressure (20 mm Hg) to leave a viscous residue which was heated under reflux with concentrated hydrochloric acid (30 ml) for six hours. The reaction mixture was washed with ether until a colourless solution was obtained. The aqueous phase was basified; extracted with ether, dried, and evaporated to give an oil which was dissolved in 5N hydrochloric acid. On evaporation a yellow oil was obtained which was triturated with petroleum ether (b.p. 62°-68° C.) to give N-isopropyl-1-[1-(4-chlorophenyl)cyclobutyl]ethylamine hydrochloride (m.p. 170°-174° C.) (Formula I R1 =Me; R2 =H; R3 =isopropyl; R4 =H; R5 =4Cl; R6 =H).
Reaction SMILES: [CH3:1][C:2]1[O:12][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Br:13][C:14]1[C:15]([Cl:22])=[C:16](F)[CH:17]=[C:18]([Cl:20])[CH:19]=1>>[ClH:20].[Br:13][C:14]1[C:15]([Cl:22])=[C:16]([O:11][CH:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]3[O:12][C:2]([CH3:1])=[CH:3][C:4]2=3)[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Cc1cc2c(o1)CNCCC2O
Reactant: Fc1cc(Cl)cc(Br)c1Cl
Product: Cc1cc2c(o1)CNCCC2Oc1cc(Cl)cc(Br)c1Cl
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 44) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2,5-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.